AI Article Synopsis
- Cystic kidney disease involves the formation of multiple fluid-filled cysts that can severely impair kidney function and lead to renal failure, as observed in TNS1-knockout mice.
- Studies using TNS1-knockout MDCK cells showed that these cells form cysts with multiple lumens and exhibit increased Mek/Erk signaling activity, which can be restored by reintroducing wild-type TNS1.
- Mek inhibitors like trametinib can reduce kidney damage in TNS1-knockout mice, suggesting that targeting the Mek/Erk pathway may offer potential therapies for cystic kidney diseases.
Article Abstract
Cystic kidney disease is the progressive development of multiple fluid-filled cysts that may severely compromise kidney functions and lead to renal failure. TNS1 (tensin-1) knockout mice develop cystic kidneys and die from renal failure. Here, we have established TNS1-knockout MDCK cells and applied 3D culture system to investigate the mechanism leading to cyst formation. Unlike wild-type MDCK cells, which form cysts with a single lumen, TNS1-knockout cysts contain multiple lumens and upregulated Mek/Erk activities. The multiple lumen phenotype and Mek/Erk hyperactivities are rescued by re-expression of wild-type TNS1 but not the TNS1 mutant lacking a fragment essential for its cell-cell junction localization. Furthermore, Mek inhibitor treatments restore the multiple lumens back to single lumen cysts. Mek/Erk hyperactivities are also detected in TNS1-knockout mouse kidneys. Treatment with the Mek inhibitor trametinib significantly reduces the levels of interstitial infiltrates, fibrosis and dilated tubules in TNS1-knockout kidneys. These studies establish a critical role of subcellular localization of TNS1 in suppressing Mek/Erk signaling and maintaining lumenogenesis, and provide potential therapeutic strategies by targeting the Mek/Erk pathway for cystic kidney diseases.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861224 | PMC |
| http://dx.doi.org/10.1038/s41419-019-2119-7 | DOI Listing |
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